The use of biodegradable polymeric nanoparticles is one way to reduce drug toxicity and degradation, while enhancing the residence time and drug concentration at the desired site of action. Biodegradability is an important attribute of a nanoparticle carrier for several reasons, including the ability to control the release of the bound molecule in a sustained, programmable way, and to provide the means for the final removal of the carrier from the body in an innocuous form. (K. S. Soppimath, T. M. Aminabhavi, A. R. Kulkarni, W. E. Rudzinski, Biodegradable polymeric nanoparticles as drug delivery devices, J. Control. Release 70 (1-2) (2001) 1-20; J. Panyam, V. Labhasetwar, Biodegradable nanoparticles for drug and gene delivery to cells and tissue, Adv. Drug Deliv. Rev. 55 (3) (2003) 329-347; A. Kumari, S. K. Yadav, S. C. Yadav, Biodegradable polymeric nanoparticles based drug delivery systems, Colloids Surf. B: Biointerfaces 75 (1) (2010) 1-18).
Biodegradable materials may be natural or synthetic and are degraded hi vivo, either enzymatically or non-enzymatically or both, to produce biocompatible, toxicologically safe by-products which are further eliminated by the normal metabolic pathways. Biomaterials used in drug delivery can be broadly classified as (1) synthetic biodegradable polymers, which includes relatively hydrophobic materials such as the a-hydroxy acids (a family that includes poly lactic-co-glycolic acid, PLGA), polyanhydrides, and others, and (2) naturally occurring polymers, such as complex sugars (hyaluronan, chitosan) and inorganics (hydroxyapatite). (Makadia H. K., et al., Poly Lactic-co-Glycolic Acid (PLGA) as Biodegradable Controlled Drug Delivery Carrier, Polymers (Basel), 2011, 3(3): 1377-1397).
Polyester PLGA is a copolymer of poly lactic acid (PLA) and poly glycolic acid (PGA). Poly lactic acid contains an asymmetric a-carbon which is typically described as the D or L form in classical stereochemical terms and sometimes as R and S form, respectively. The enantiomeric forms of the polymer PLA are poly D-lactic acid (PDLA) and poly L-lactic acid (PLLA). PLGA is generally an acronym for poly D,L-lactic-co-glycolic acid where D- and L-lactic acid forms are in equal ratio. (Makadia et al, 2011)
PLGA can be processed into almost any shape and size, and can encapsulate molecules of virtually any size. It is soluble in wide range of common solvents including chlorinated solvents, tetrahydofuran, acetone or ethyl acetate. In water, PLGA biodegrades by hydrolysis of its ester linkages. Due to the hydrolysis of PLGA, parameters that are typically considered invariant in a solid formulation can change with time, such as the glass transition temperature (Tg), moisture content and molecular weight. The change in PLGA properties during polymer biodegradation influences the release and degradation rates of incorporated drug molecules. PLGA physical properties themselves depend upon multiple factors, including the initial molecular weight, the ratio of lactide to glycolide, the size of the device, exposure to water (surface shape) and storage temperature. Mechanical strength of the PLGA is affected by physical properties such as molecular weight and polydispersity index. These properties also affect the ability to be formulated as a drug delivery device and may control the device degradation rate and hydrolysis. The type of drug may also play a role in setting the release rate. Mechanical strength, swelling behavior, capacity to undergo hydrolysis and subsequently biodegradation rate of the polymer are directly influenced by the degree of crystallinity of the PLGA, which is further dependent on the type and molar ratio of the individual monomer components in the copolymer chain. Crystalline PGA, when co-polymerized with PLA, reduces the degree of crystallinity of PLGA and as a result increase the rate of hydration and hydrolysis. As a rule, higher content of PGA leads to quicker rates of degradation with an exception of 50:50 ratio of PLA/PGA, which exhibits the fastest degradation, with higher PGA content leading to increased degradation interval below 50%. Degree of crystallinity and melting point of the polymers are directly related to the molecular weight of the polymer. The Tg (glass transition temperature) of the PLGA. copolymers are reported to be above the physiological temperature of 37° C. and hence are glassy in nature, thus exhibiting fairly rigid chain structure. The Tg of PLGAs decrease with a decrease of lactide content in the copolymer composition and with a decrease in molecular weight. (Makadia et al. 2011)
Various types of block copolymers of polyesters with poly ethylene glycol (PEG) have been developed in response to the need for better delivery formulations to incorporate a variety of drugs and methods of administration. PL-GA/PEG block copolymers can be processed as a diblock (PLGA-PEG) or tri-block (PLGA-PEG-PLGA) molecules. In diblock types, PEG chains orient themselves towards the external aqueous phase in micelles, thus surrounding the encapsulated species. This layer of PEG acts as a barrier and reduces the interactions with foreign molecules by steric and hydrated repulsion, giving enhanced shelf stability. (Makadia et al, 2011)
PLGA copolymer undergoes degradation by hydrolysis or biodegradation through cleavage of its backbone ester linkages into oligomers and, finally monomers. The degradation process for these polymers is mainly through uniform bulk degradation of the matrix where the water penetration into the matrix is higher than the rate of polymer degradation. Furthermore, the increase of carboxylic end groups as a result of biodegradation autocatalyses the process. The degradation of PLGA copolymer is the collective process of bulk diffusion, surface diffusion, bulk erosion and surface erosion. Since there are many variables that influence the degradation process, the release rate pattern is often unpredictable. The biodegradation rate of the PLGA copolymers are dependent on the molar ratio of the lactic and glycolic acids in the polymer chain, molecular weight of the polymer, the degree of crystallinity, and the Tg of the polymer. The release of drug from the homogeneously degrading matrix is more complicated. In general, the initial burst of drug release is related to drug type, drug concentration and polymer hydrophobicity. Drug on the surface, in contact with the medium, is released as a function of solubility as well as penetration of water into polymer matrix. Random scission of PLGA decreases molecular weight of polymer significantly, but no appreciable weight loss and no soluble monomer product are formed in this phase. In the second phase, drug is released progressively through the thicker drug depleted layer. The water inside the matrix hydrolyzes the polymer into soluble oligomeric and monomeric products. This creates a passage for drug to be released by diffusion and erosion until complete polymer solubilization. Drug type also plays an important role here in attracting the aqueous phase into the matrix. (Makadia et al. 2011)
Several factors can affect degradation of PLGA nanoparticles including: polymer composition; crystallinity; weight average molecular weight of the polymer; type of drug; ratio of surface area to volume of the polymer; pH; and drug loading, In general, the PLGA degradation and the drug release rate can be accelerated by greater hydrophilicity, increase in chemical interactions among the hydrolytic groups, less crystallinity and larger volume to surface ratio of the device, (Makadi a et al. 2011)
Previous studies suggest that both blood clearance and uptake by the mononuclear phagocyte system (MPS) may depend on dose and composition of PLGA carrier systems. (Panagi Z., et al., Effect of dose on the biodistribution and pharmacokinetics of PLGA and PLGA-mPEG nanoparticles. Int J Pharm., 2001 Jun. 19; 221(1-2): 143-52). The degradation of the PLGA carriers is quick on the initial stage (around 30%) and slows eventually to be cleared by respiration in the lung. (Bazile D V, et al., Body distribution of fully biodegradable [14C]-poly(lactic acid) nanoparticles coated with albumin after parenteral administration to rats. Biomaterials, 1992; 13(15): 1093-102). Surface modification via incorporation of surface modifying agents can significantly increase blood circulation half-life. (Makadia et al. 2011)
Glutathione (GSH) is a tripeptide antioxidant that protects tissues from reactive oxidative species (ROS) as well as other types of oxidative damage. GSH interacts with transmembrane proteins located in the brain that are involved in the active transport of certain substances across the blood brain barrier (BBB). The BBB is a physical interface in the central nervous system (CNS) between the blood and nervous tissue which greatly limits the availability of drugs to the brain. Coating drug-encapsulating nanoparticles with glutathione facilitates the nanoparticles crossing the BBB which allows for targeted therapies of brain-related disorders. (Grover A., et al., Blood-Brain Barrier Permeation of Glautathione-Coated Nanoparticle, SOJ Pharm PharmSci, 2014, 1(1):4)
Afobazole (5-ethoxy-2[2-(morpholine)-ethylthio]benzimidazole), a drug currently used in Russia to treat anxiety and panic disorders, was recently shown to be both a σ-1 and σ-2 receptor agonist, and provides neuroprotection in an in vitro ischemia model (Cuevas et al., 2011a; Cuevas et al., 2011b). Unlike ANAVEX2-73, afobazole does not interact with muscarinic receptors (Seredenin et al., 2009).
Activation of σ-1 receptors by afobazole results in a decrease in ischemia-induced Ca2+ overload, which is due in part to inhibition of NMDA channel activation (Katnik et al., 2006; Cuevas et al., 2011a). Previous studies have suggested other mechanisms for the neuroprotective properties of afobazole, including decreased caspase-3 activation and reduced oxidative stress (Zenina et al., 2005; Antipova et al., 2010).
Afobazole currently has a short half-life in vivo and has limited brain penetration. This drug is currently used in once a day dosing for the treatment of anxiety in Europe and is being studied for the treatment of other diseases such as stroke, multiple sclerosis and Alzheimer's disease.
Given the obstacles of treatment with afobazole as described above, what is needed is a drug formulation which can readily cross the blood brain barrier (BBB) and enhance the residence time and drug concentration at the targeted site.